title: The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma.
abstract: The recent clinical success of targeted therapies in melanoma directed at the oncogene BRAF validates the concept of targeting oncogenes. The p16-cyclin D-CDK4/6-retinoblastoma protein pathway (CDK4 pathway) is dysregulated in 90% of melanomas, and is, therefore, an obvious therapeutic target for this disease. The main outcome of CDK4 activation is the phosphorylation and, thus, inhibition of the retinoblastoma protein leading to G1-S cell-cycle transition. In addition, CDK4 directly phosphorylates other proteins that promote cell-cycle progression and inhibit both cell senescence and apoptosis. In preclinical studies, the response to CDK4 inhibition correlates with genomic changes that increase CDK4 activity, most notably where the tumor suppressor CDKN2A (p16(INK4A)) is deleted. A central question is whether melanomas with activating events in the CDK4 pathway have become "addicted" to this signaling pathway, in which case inhibition of CDK4 would not simply induce cell-cycle arrest but induce cell death and tumor regression. Recently, a number of selective CDK4/6 inhibitors have entered clinical trials, and these compounds are showing great promise in that they are well tolerated and show clinical benefit. This review discusses the CDK4 pathway, its dysregulation in melanoma, the consequences of CDK4 pathway inhibition, and potential novel combinational strategies for the treatment of melanoma.
authors.affiliation: Authors' Affiliations: Sir Peter MacCallum Department of Oncology and Departments of Pathology and Biochemistry and Molecular Biology, University of Melbourne, Parkville; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy; Molecular Oncology Laboratory, Oncogenic Signaling and Growth Control Program; Translational Research Laboratory, Cancer Therapeutics Program; and Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Sheppard
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D051358:Cyclin-Dependent Kinase 4